To understand the importance of cell cycle regulators, specifically Cdk4, during beta-cell regeneration we used the streptozotocin (STZ)-induced model of diabetes. We speculated that this kinase may play a crucial role in the regenerative process triggered by STZ. To examine this possibility, we injected STZ in age-matched and sex-matched Cdk4+/+ and Cdk4R24C/R24C (Cdk4R/R) mice. Less than two-month old mice were used in this experiment since at that age both Cdk4+/+ and Cdk4R/R strains of mice exhibit similar islet mass and blood glucose level, which allows analysis of the effects of STZ more accurately. Mice were injected intraperitoneally with STZ and monitored by analyses of blood glucose levels for evidence of hyperglycemia. Within 48 hours of STZ injection, all of the control Cdk4+/+ littermates developed hyperglycemia which persisted until either death or the need to sacrifice the mice due to poor health Dramatically and in contrast, none of the Cdk4R/R mice developed severe hyperglycemia or diabetes during the entire 14-day observation period. Immunohistochemistry analysis revealed that at the beginning of STZ treatment both Cdk4+/+ and Cdk4R/R mice have comparable islet mass. As early as 12 hours into STZ treatment islets from both the Cdk4R/R and Cdk4+/+ mice showed evidence of islet atrophy. By 48 hours after STZ treatment, majority of islets from Cdk4+/+ mice show evidence of extensive atrophy with very few easily detectable islets. In contrast, islets from Cdk4R/R mice appear to maintain their islet mass and by 24-48 hours majority of the islets from Cdk4R/R mice showed close to normal architecture and islet mass. During the period of 24-48 hours of STZ treatment we see evidence of a dramatic repopulation of the islet architecture and more significantly an increase in insulin immunofluorescence suggesting that the Cdk4R/R mice have a close to normal beta-cell repertoire. Recent studies have demonstrated the ability of beta-cells to undergo self-duplication, and thus we examined if this mechanism was responsible for the observed recovery of beta-cell mass in Cdk4R24C/R24C mice in response to STZ. To this end, we injected the DNA-analog BrDU into Cdk4+/+ and Cdk4R/R mice and harvested their pancreas 6-hours after BrDU administration. Similar numbers of BrDU-labeled cells were observed in untreated Cdk4R/R islets compared to untreated Cdk4+/+ islets indicative of a similar -cell proliferation rate in these mice at the beginning of the experiment. In contrast, to the severely reduced to non-existent BrDU-labeled cells in islets from 48-hour STZ treated Cdk4+/+ mice, we observed a significant increase in BrDU-labeled cells in islets from 48-hour STZ treated Cdk4R/R mice. These results elucidate that increased beta-cell proliferation leads to efficient reconstitution of beta-cell mass in Cdk4R/R islets in response to a STZ. There is much debate as to the post-natal origins of beta-cells and the mechanisms that lead to reconstitution of beta-cell mass. It has been reported that (1) beta-cells turn over rather slowly since they have a long-lifespan and (2) that replication of pre-existing beta-cells is the primary mechanism that repopulates the beta-cell compartment. While beta-cell replication appears to be a primary mechanism responsible for the increase in beta-cell mass there is considerable evidence in favor of the contribution of the pancreatic ductal epithelium in generation of new beta cells via a process termed as neogenesis. The STZ model, considering the beta-cell specificity of STZ, is suitable to study the dynamics of beta-cell proliferation and the role of pre-existing beta-cells in the regenerative process. However, since majority of beta-cells are believed to be restricted to the endocrine islet compartment, the STZ model is for the most part limiting to the examination of the involvement of the ductal epithelium in pancreatic regeneration, including to study beta-cell neogenesis. To circumvent this bias, we used a distinct model of regeneration, partial pancreatectomy (PX), where the processes of beta-cell replication within the islets and neogenesis within the islets and in the surrounding pancreatic ductal epithelium can be analyzed. PX, either partial, sub-total and total, has been widely used to study pancreatic regeneration and the degree of PX determines the extent of glucose intolerance, onset of diabetes and the potential reconstitution of pancreatic mass. Here we performed a 70% PX on the two-month old sex-matched Cdk4+/+ and Cdk4R/R mice and evaluated their pancreas regenerative potential. Consistent with prior publications we did not observe glucose intolerance in either the Cdk4+/+ and Cdk4R/R mice after 70% PX. At the time of PX, the beta-cell mass in Cdk4+/+ and Cdk4R/R mice is comparable and five days (5d) after PX we also did not observe a substantial change in the overall beta-cell mass in either the Cdk4+/+ and Cdk4R/R mice . However, beta-cell mass was significantly increased in the Cdk4R/R mice, compared to that observed in Cdk4+/+ mice, 14d after PX. These observations indicate that inheritance of an activated Cdk4R24C kinase leads to enhanced beta-cell regeneration. No significant difference in beta-cell proliferation, as assayed by quantifying BrDU positive and Insulin Positive cells (BrDU+:Ins+), was observed in Cdk4+/+ and Cdk4R/R pancreas before and 1d after PX. At 2d post-PX we observed an increase in beta-cell proliferation in both the Cdk4+/+ and Cdk4R/R mice, although the degree of beta-cell proliferation between the two groups of mice were not significant. However, at d14 post-PX, a significant increase in beta-cell proliferation was seen in Cdk4R/R pancreas. In contrast the extent of beta-cell proliferation in Cdk4+/+ pancreas at 14d post-PX was similar to that seen at 2D post-PX. Taken together these observations indicate that in the Cdk4+/+ mice compensatory beta-cell proliferation reaches maximal potential by 2d post-PX, in contrast to the beta-cell proliferation in Cdk4R/R mice that continues until 14d post-PX. In addition, we also observe Pdx1+ cells in the pancreatic ductal epitlelium that are suggestive of ongoing neogenesis. In support we observe robust proliferation of ductal epithelial cells along with a rise in the number of islet-like cell clusters that are insulin positive. Together, these observations are indicative of replication of pre-existing beta cells and neogeneis from the ductal epithelium as process that regulate adult beta cell mass reconstitution.